tbuckley/cabot-search huggingface dataset:
P030: Baseline IgM amount can identify patients with adverse outcome despite a PET-2 adapted treatment in classical Hodgkin Lymphoma: results from a real-life single-center study i
Authors: Alessandra Romano, Claudio Cerchione, Gabriella Santuccio, Marialudovica Le Moli, Annalisa Chiarenza, Amalia Figuera, Giovanna Motta, L. Caruso, Sofia Lanza, A. Petronaci, S. Poidomani, Massimo Ippolito, Francesco Di Raimondo
Journal: HemaSphere (2022)

Background: Hodgkin Lymphoma is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune suppressive effect that advances progression of disease. Immunoglobulin M is first antibody isotype to be produced during an immune response, but it plays also an immunoregulatory role, therefore we investigated if it could have any clinical impact on prognosis. Experimental design: In this retrospective, observational, single – center study, we evaluated 212 newly diagnosed Hodgkin Lymphoma (HL) patients, including 132 advanced stage cases, with a median follow up of 60.3 months (range 60–204); 109 (51%) were men, with a median age of 31 years (range 15–77), 64 patients showed bulky disease, while 119 suffered from B symptoms at the onset. The median baseline values for IgM, IgA and IgG were, respectively: 86.0 (range 5.0–336.0 mg/dL), 197.5 (range 5.0–336.0 mg/dL) and 1110.00 (range 157.0–2763.0 mg/dL). 49/212 (23%) patients had a baseline IgM value lower than 50mg/dL. White blood cell count and type were determined by electrical impedance method. Nephelometry was used for immunoglobulins quantification. Results: PFS at 60 months was 54.1% versus 81.1 % respectively in patients with IgM ≤50 mg/dL or IgM>50 mg/dL (p<0.001). A level of 50 mg/dl of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity in predicting achievement of complete response in the whole cohort (area under curve - AUC - 0.62, p=0.013). In multivariate analysis, only baseline IgM ≤50 mg/dl and presence of large nodal mass (< 7 cm) were independent baseline variables able to predict clinical outcome while after two cycles of treatment only IgM ≤50 mg/dl at baseline and PET-2 status were independent predictors of PFS. Thus, we stratified the advanced stage patients in three groups based on clinical variables available at diagnosis: low risk group was defined as absence of LNM and baseline IgM >50; standard-risk was defined by either presence of LNM or baseline IgM ≤50 mg/dL; high risk group was defined by both presence of LNM and IgM ≤50 mg/dL at baseline. The 60-months PFS estimates were significantly different among the three groups, respectively 83.5, 59.5 and 40.0%, p=<0.0001. Conclusion: IgM amount at diagnosis is a valuable prognostic factor much earlier than PET-2 and it can also provide information in PET-2 negative patients. This can help identify at baseline different HL classes at risk of treatment failure.
P008: Impact of bone marrow involvement on early PET response and progression-free survival in the HD18 trial for patients with advanced-stage Hodgkin lymphoma
Authors: Conrad-Amadeus Voltin, Stefanie Kreissl, Helen Kaul, Ina Bühnen, Jasmin Mettler, Thomas Pabst, Dennis A. Eichenauer, Michael Fuchs, Volker Diehl, Markus Dietlein, Andreas Engert, Peter Borchmann, Carsten Kobe
Journal: HemaSphere (2022)

Background: The prognostic role of bone marrow (BM) involvement in advanced-stage Hodgkin lymphoma is unclear, particularly for patients receiving intensive first-line treatment. We thus retrospectively examined its impact on early response and progression-free survival (PFS) among individuals receiving escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) in the HD18 trial. Patients and Methods: A total of 424 individuals were suitable for analysis, of which 124 (29%) had BM involvement according to initial positron emission tomography (PET). Patient outcome was measured by PET response after 2×eBEACOPP and five-year PFS rate. Results: After 2×eBEACOPP, 79 of the BM PET-negative individuals (26%) and 26 of the BM PET-positive patients (21%) were found to be PET-positive (odds ratio [OR] 0.74, P=0.25). The five-year PFS rate was 90.7% in BM PET-negative individuals and 91.8% for BM PET-positive patients (hazard ratio 0.82, P=0.6). In our BM PET-positive subgroup, nine (16%) of the 56 subjects with one or two sites of skeletal uptake were PET-positive after 2×eBEACOPP as compared to 17 (25%) of the 68 individuals showing three or more BM lesions (OR 1.74, P=0.23). Conclusions: The present analysis demonstrates that BM involvement, irrespective of its extent, does not lead to increased risk for a positive interim PET result or inferior PFS in advanced-stage Hodgkin lymphoma patients undergoing eBEACOPP treatment. Skeletal lesions cannot therefore be considered as an additional prognostic marker of therapy failure or disease recurrence for individuals receiving intensive first-line treatment.
P103: Comparison of PET-derived parameters in program cell death-1 inhibitor and CD30 antibody drug conjugate-based therapies in patients with advanced stage cHL: A single center experience.
Authors: Serageldin Kamel, Lucia Martiniova, Eslam Aboismail, Joo Schmidt, Sairah Ahmed, Ranjit Nair, Raphael E. Steiner, Michael L. Wang, Sarita Soebianto, Gregory Ravizzini, Tinsu Pan, Hun Ju Lee
Journal: HemaSphere (2022)

Table 1: Patient characteristics and PET-derived parameters Background: Advanced-stage classical Hodgkin’s lymphoma (cHL) is a curable malignancy, however up to 25% of patients may relapse following frontline multiagent-chemotherapy. Novel treatment options such as PD-1 inhibitors and antibody-drug conjugates (ADC) have demonstrated high efficacy with favorable safety profiles in frontline and relapsed cHL. Early reduction in volumetric and metabolic PET parameters have been reported as effective predictors of outcome in cHL. Here, we describe the changes in metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) after two cycles of therapies containing nivolumab, brentuximab vedotin (Bv), or both in advanced cHL. Methods: We retrospectively enrolled subjects with newly diagnosed, advanced stage cHL who received therapy in three protocols: Bv-nivolumab-AD, Bv-AVD, or nivolumab-AVD. All protocols did not allow for radiation consolidation. Baseline (PET0) and interim PET after two cycles (PET2) were analyzed and cHL lesions were segmented using a threshold of 41% of the SUVmax. MTV, TLG, and SUVmax were recorded at both time-points and percentage changes were calculated as ΔMTV, ΔTLG, and ΔSUVmax, respectively. Summary statistics were reported, and Kurskal-Wallis test was used to compare PET-parameters among the groups with P<0.05 considered statistically significant. Results: A total of 27 subjects were included in the final analysis. Subjects were treated with Bv-nivolumab-AD (n=16), Bv-AVD (n=5) and nivolumab-AVD (n=6). The distribution of MTV, TLG, and SUVmax values at PET0 and PET2 were not significantly different across the three groups. The median (IQR) ΔMTV of all study subjects was 100% (99.2%–100%), ΔTLG 100% (99.69%–100%) and ΔSUVmax 100% (68.1%–100%). Initial observation suggested that subjects receiving nivolumab-AVD had less tumor burden reduction rate compared to Bv-nivolumab-AD and Bv-AVD groups. However, this difference was not statistically significant (P=0.10) (Table 1) Conclusion: This is the first report to describe PET-derived metabolic changes in advanced stage cHL patients receiving nivolumab and/or Bv-based regimens. Our initial results suggest a significant and comparable reduction in MTV, TLG, and SUVmax among the three treatment groups. The limited sample size did not confirm an initial observation of higher reductions in patients receiving Bv-based strategies. Future studies are needed to further explore and validate these findings.
P107: Effect of Brentuximab Vedotin Addition to Chemotherapy and Prognostic Factors in Patients with Relapsed/Refractory Hodgkin Lymphoma: a Large Multi-Trial Analysis Based on Individual Patient Data
Authors: Julia Driessen, Fer De Wit, Alex F. Herrera, Pier Luigi Zinzani, Ann S. Lacasce, Peter D. Cole, Craig H. Moskowitz, Ramón. García Sanz, Michael Fuchs, Horst Müller, Peter Borchmann, Armando Santoro, Heiko Schöder, Josée. M. Zijlstra, Barbara A. Hutten, Alison J. Moskowitz, Marie José Kersten
Journal: HemaSphere (2022)

Figure 1: Overview of included studies, patient characteristics of the matched cohort and Kaplan-Meier results of progression free survival and overall survival analysis in the matched cohort. Background: The aims of this study were to investigate the effect of brentuximab vedotin (BV) addition to salvage chemotherapy compared to chemotherapy alone on progression free survival (PFS), overall survival (OS) and complete metabolic response (CMR) rate prior to autologous stem-cell transplant (ASCT), and to identify prognostic factors in patients with a first relapse or primary refractory classical Hodgkin lymphoma (R/R cHL). Methods: We collected individual patient data of 770 transplant eligible R/R cHL patients treated in prospective clinical trials, of whom n=386 were treated with BV and chemotherapy (BV-cohort), and n=384 with chemotherapy alone (Chemo-cohort), followed by ASCT [Fig1A]. The BV- and Chemo-cohorts were matched by propensity scores on baseline characteristics (i.e. relapsed/refractory, bulky disease, extranodal disease, stage I-II/III-IV, B symptoms and first-line treatment with BEACOPP). Matching was repeated 2000 times as internal validation and mean results are presented. Primary refractory disease was defined as no complete response on first-line treatment. Results: After matching, there were no statistically significant differences in baseline characteristics between the cohorts [Fig1B]. The 3-year PFS was 73% (95%CI: 67–79%) in the BV-cohort compared to 67% (61–74%) in the Chemo-cohort (p=0.14) [Fig1C] and the 3-year OS was 93% (89–96%) versus 80% (75–86%) (p<0.001), respectively [Fig1D]. Primary refractory patients did not show any difference in PFS between the BV- and Chemo-cohorts (p=0.78), while patients with relapsed disease showed a significantly higher PFS in the BV-cohort (p=0.037) [Fig1E+F]. Logistic regression showed a significantly higher CMR rate for the BV-cohort compared to the CMR rate after BeGEV or ICE only (71.2% versus 63.1%; p=0.021), but there was no significant difference when compared to ICE-GVD (71.2% versus 76.4%; p=0.43). Cox regression for 3-year PFS showed high prognostic value for not achieving a CMR pre-ASCT (HR 2.0; p=0.002), stage III/IV (HR 2.0; p<0.001), B-symptoms (HR 1.8; p<0.001) and primary refractory disease (HR 1.7; p<0.001). Conclusions: The addition of BV to salvage chemotherapy followed by ASCT seems to increase PFS in relapsed, but not in primary refractory cHL patients. This suggests that in patients who are chemotherapy resistant other treatment modalities, such as checkpoint inhibitors (CPI), should be considered.
T028: Single-cell RNA sequencing reveals the interplay between circulating CD4 T cells, B cells and cancer-associated monocytes in classic Hodgkin lymphoma treated with PD-1 blockade
Authors: Julia Paczkowska, Ming Tang, Kyle T. Wright, Li Song, Vignesh Shanmugam, Kelsey Luu, Emma L. Welsh, Fathima Zumla Cader, Elisa Mandato, Jing Ouyang, Gali Bai, Lee Lawton, Scott Rodig, X Shirley Liu, Margaret A. Shipp
Journal: HemaSphere (2022)

Classic Hodgkin lymphoma (cHL) is a largely MHC class I-negative tumor with recurrent 9p24.1/ PD-L1/ PD-L2 copy gains and the highest reported response rates to PD-1 blockade. In cHL, the efficacy of PD-1 blockade is closely associated with Hodgkin and Reed-Sternberg (HRS) cell expression of MHC class II, highlighting the potential role of CD4+ T-cell effectors and additional non-MHC class I-mediated mechanisms of tumor cell killing. We utilized scRNA sequencing to characterize the peripheral immune response to PD-1 blockade and more broadly define non-CD8+ dependent mechanisms of immune evasion in cHL. Peripheral blood mononuclear cells were obtained from 20 patients with relapsed/refractory (R/R) cHL treated with PD-1 blockade (nivolumab) on the CheckMate 205 clinical trial (cycle 1 day 1 [C1D1] and cycle 4 day 1 [C4D1]), 11 patients with newly diagnosed, previously untreated cHL and 13 healthy donors. Unlike healthy donors, all evaluated patients with cHL had circulating IFN stimulated adaptive and innate populations, including several distinct CD4+ T-cell effectors and an NK cell subset with reduced cytotoxic potential, and decreased numbers of B cells at all stages of differentiation. Patients with the most favorable responses to PD-1 blockade had: 1) significantly increased CD4+ T-cell receptor diversity and more abundant naïve/ central memory subsets; and 2) significantly higher B-cell receptor diversity and increased numbers of circulating B cells. The most abundant circulating CD3- population in patients with cHL was a newly identified monocyte subset with increased expression of multiple immunosuppressive and tumorigenic cytokines and chemokines, PD-L1 and SIRPa. This newly identified monocytic population was virtually absent from the blood of healthy donors. RNAscope analysis of the intact tumor microenvironment localized these tumor-infiltrating monocytes/macrophages to the immediate proximity of HRS cells. Monocytes from patients whose disease progressed following PD-1 blockade expressed significantly higher levels of immunosuppressive cytokine/chemokine signature which led to the development of a predictive transcriptional assay. We identified a comparable circulating monocyte population and transcriptional signature associated with unresponsiveness to PD-1 blockade in an additional solid tumor underscoring the broad-based significance of these findings.
P095: Personalised Modelling of Quality-Adjusted Survival Benefit and Cost-Effectiveness of using Proton Beam Therapy inthe Treatment of Intermediate-Stage Hodgkin Lymphoma in England
Authors: David Jones, Rebecca Shakir, Paolo Candio, Johanna Ramroth, Jane Wolstenholme, Alastair Gray, David Cutter, Georgios Ntentas
Journal: HemaSphere (2022)

Figure 1: Box plots of the estimated difference in quality-adjusted life years between PBT and VMAT by age, sex, smoking status, and discount rate. Background: Radiotherapy (RT) for Hodgkin lymphoma leads to the incidental irradiation of organs-at-risk (OAR) which may confer excess risks of second primary cancers as well as cardiovascular disease. Comparative dosimetry studies show that proton beam therapy (PBT) may reduce OAR irradiation compared to conventional photon-RT, but the benefit in terms of risk reduction is highly heterogeneous within cohorts of comparatively planned patients. Furthermore, PBT is likely to be more expensive and treatment capacity is limited. In this study, we aim to inform the use of PBT for intermediate-stage Hodgkin lymphoma (ISHL) in England by modelling the life course and healthcare costs of 606 illustrative patients. Methods: A microsimulation model simulating the life-time course of ISHL, background mortality, and incidence and mortality of late effects was used to estimate comparative quality-adjusted life years (QALYs) lived and healthcare costs after consolidative PBT or photon-RT, both in deep inspiration breath hold (DIBH). Outcomes were compared for the illustrative patients who covered a spectrum of clinical presentations, varying by two age strata (20y and 40y), sex, smoking status (never, former, and current), and 61 pairs of OAR radiation doses from a comparative planning study. Both undiscounted and discounted (3.5% annually) outcomes were estimated. We performed threshold analysis to calculate the maximum additional cost of PBT over photon-RT that might be considered cost-effective by the UK’s National Institute for Health and Care Excellence (NICE). Findings: Box plots of the estimated difference in QALYS between PBT and photon-RT by age, sex, smoking status, and discount rate are given in Figure 1. Current smokers benefited the most, averaging 0.583 undiscounted QALYs (range -0.339 to 2.151) and 0.137 discounted QALYs (range -0.059 to 0.620) whereas never smokers benefited the least, averaging 0.071 undiscounted QALYs (range -0.198 to 0.499) and 0.016 discounted QALYs (range -0.030 to 0.085). For the gain in discounted QALYs to be considered cost-effective at NICE’s £30,000/per QALY threshold, PBT would have to cost, at most, £4458 more than photon-RT for current smokers and £598 for never smokers. This is likely far below the cost of PBT over conventional photon-RT.
P035: CRISPR/Cas9-mediated knockout reveals an important role of CD30 in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma
Authors: Annika L. Kilian, Anna Lollies, Marc A. Weniger, Ralf Küppers
Journal: HemaSphere (2022)

The malignant Hodgkin- and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) highly and consistently express CD30 on their cell surface, which is used for its diagnosis and since recently targeted therapy with drug-conjugated CD30-specific antibodies. However, the role of CD30 in the pathogenesis of cHL is not well understood and controversially discussed. We established a CRISPR/Cas9 system in CD30-positive lymphoma cell lines and confirmed efficient knockout of CD30. Characterization of CD30-depleted cHL cell lines identified a growth disadvantage under competitive growth conditions and CD30-knockout cultures showed increased cell death, which was at least partly mediated by apoptosis. Influences of CD30 on the activity of a main signaling pathway driving cHL lymphomagenesis, i.e., NF-κB signaling, were detected. Furthermore, contribution of CD30 signaling to the high MYC activation signature of cHL cell lines was identified. These results point to an important role of CD30 expression by HRS cells for the pathobiology of cHL.
P048: Predictors of risk of relapse in classic Hodgkin lymphoma by flow cytometry
Authors: Jonathan Fromm, Claire Tang, Kikkeri N. Naresh
Journal: HemaSphere (2022)

Background: Classic Hodgkin lymphoma (CHL) is a highly treatable lymphoid malignancy, characterized by rare neoplastic Hodgkin Reed–Sternberg cells (HRS-cells) embedded in a prominent reactive infiltrate. Despite current therapies, about 20% of patients relapse within five years of standard treatment. Identifying patients at risk of subsequent relapse will help develop novel therapeutic strategies for such high-risk patients. Methods: Using multiparametric flow cytometric analysis, we retrospectively evaluated the impact of the proportion of HRS-cells; the proportion of HRS-cells with T-cell rosettes; proportions of T-cells, B-cells, neutrophils, and eosinophils; proportions of activated T-cells, and activated B-cells; and CD4:CD8 ratio on the likelihood of disease relapse in a cohort of 62 patients. Results: The median follow-up period was 69.5 months. Patients >35 years of age had a significantly higher percentage of HRS-cells (P=0.017) and a significantly lower percentage of B cells (P=0.017). The nodular sclerosis subtype had a significantly higher percentage of B-cells (P=0.046) and activated B-cells (P=0.03). Patients who experienced disease relapse (DR) had a significantly lower percentage of rosetted HRS-cells as compared to patients who achieved sustained clinical remission (SCR) (P=0.022; Figure 1). Patients experiencing DR also had a marginally lower B-cell% (P=0.11), and higher neutrophil% (P=0.107) and eosinophil% (P=0.095). The proportion of SCR and DR subsets did not differ by histological subtypes, disease stage, or age-groups. Conclusions: CHL demonstrates a prominent tumor microenvironment (TME) where HRS-cells and the TME result in HRS-cells receiving pro-survival signals and dampening the antitumor immune responses. In our study, patients who experienced DR had a lower proportion of HRS-cells rosetted by T-cells; we hypothesize that HRS-cells in biologically advanced/aggressive CHL are less dependent on its intimate contact or interactions with the T-cells for survival and growth. Likewise, a non-significant higher proportion of eosinophils and neutrophils in the TME of CHL patients who experienced DR was observed, possibly due to the ability of these cells to promote proliferation and growth of HRS-cells. Our study also identifies novel quantifiable biomarkers in CHL. Larger independent studies and multi-institutional studies are essential to validate our findings.
P071: First results of cardiovascular screening in a survivorship care program for Hodgkin lymphoma survivors in the Netherlands
Authors: Eline M.J. Lammers, Annelies Nijdam, Josée. M. Zijlstra, Cécile P.M. Janus, Roel J. De Weijer, Flora E. Van Leeuwen, Berthe M. P. Aleman
Journal: HemaSphere (2022)

Figure 1: the figure caption is included in the figure Background: Hodgkin lymphoma (HL) survivors are at increased risk of cardiovascular diseases (CVD) due to former treatment. In 2013, we started survivorship care for 5-year HL survivors at Dutch BETER clinics, where screening for CVD and associated risk factors according to uniform guidelines was implemented. Eligibility criteria for cardiovascular screening include: 1) age at HL treatment ≤60 and current age ≤70 years 2) treatment with mediastinal radiotherapy with/without anthracyclines (irrespective of dose) or anthracycline cumulative dose equivalent to doxorubicin ≥300 mg/m2. We assessed adherence to screening guidelines and the yield of previously undiagnosed (risk factors for) CVD in the screening program. Methods: Data on patient and treatment characteristics and cardiovascular screening were collected retrospectively from medical records for 5-year HL survivors who visited the BETER outpatient clinic at three university medical centers in 2013–2020. Results: We identified 240 patients, of whom 184 (76.7%) were eligible for cardiovascular screening (mean age at start follow-up 47.7 years). In eligible patients, CVD screening was performed according to the guidelines: physical examination (65.8%), lipids (86.4%), (NT)proBNP (82.1%), glucose (85.3%), electrocardiogram (97.3%) and echocardiography (96.7%). Screening yielded the following new diagnoses in eligible patients (Figure 1): hypertension (4.3%), dyslipidemia (10.3%), heart failure (1.1%), cardiomyopathy (1.6%), coronary artery disease (1.1%), conduction disorder/dysrhythmia (4.3%), pericarditis (0.5%), mild aortic or mitral valve insufficiency or stenosis (31.0%) and severe aortic or mitral valve insufficiency or stenosis (2.7%). Left ventricular ejection fraction (LVEF) was available for 87 eligible patients, of whom 9 (10.3%) had a LVEF <50%. Echocardiography was also performed in 32 out of 56 (57.1%) non-eligible patients: 21.9% had a new mild valve dysfunction, 3.1% had a new severe valve dysfunction. Conclusion: Adherence to the screening guidelines was reasonable. A substantial number of new (risk factors for) cardiovascular conditions were diagnosed in the Dutch BETER screening program for HL survivors, also in non-eligible survivors. Future studies are needed to confirm findings in a broader population and to determine whether screening is effective in reducing burden of disease associated with late cardiovascular effects and in improving survivor’s quality of life.